A cell biological view of Toll-like receptor function: regulation through compartmentalization (original) (raw)

• Medzhitov, R. Recognition of microorganisms and activation of the immune response. Nature 449, 819–826 (2007).
  Article CAS Google Scholar
• Takeda, K., Kaisho, T. & Akira, S. Toll-like receptors. Annu. Rev. Immunol. 21, 335–376 (2003).
  Article CAS Google Scholar
• Janeway, C. A. Jr. Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb. Symp. Quant. Biol. 54, 1–13 (1989).
  Article CAS Google Scholar
• Medzhitov, R. & Janeway, C. A. Jr. Innate immunity: the virtues of a nonclonal system of recognition. Cell 91, 295–298 (1997).
  Article CAS Google Scholar
• Jin, M. S. et al. Crystal structure of the TLR1–TLR2 heterodimer induced by binding of a tri-acylated lipopeptide. Cell 130, 1071–1082 (2007).
  Article CAS Google Scholar
• Kim, H. M. et al. Crystal structure of the TLR4–MD-2 complex with bound endotoxin antagonist eritoran. Cell 130, 906–917 (2007).
  Article CAS Google Scholar
• Liu, L. et al. Structural basis of Toll-Like receptor 3 signaling with double-stranded RNA. Science 320, 379–381 (2008).
  Article CAS Google Scholar
• Iwasaki, A. & Medzhitov, R. Toll-like receptor control of the adaptive immune responses. Nature Immunol. 5, 987–995 (2004).
  Article CAS Google Scholar
• Kawai, T. & Akira, S. TLR signaling. Cell Death Differ. 13, 816–825 (2006).
  Article CAS Google Scholar
• Akashi, S. et al. Lipopolysaccharide interaction with cell surface Toll-like receptor 4–MD-2: higher affinity than that with MD-2 or CD14. J. Exp. Med. 198, 1035–1042 (2003).
  Article CAS Google Scholar
• Husebye, H. et al. Endocytic pathways regulate Toll-like receptor 4 signaling and link innate and adaptive immunity. Embo J. 25, 683–692 (2006).
  Article CAS Google Scholar
• Underhill, D. M. et al. The Toll-like receptor 2 is recruited to macrophage phagosomes and discriminates between pathogens. Nature 401, 811–815 (1999).
  Article CAS Google Scholar
• Marshak-Rothstein, A. Toll-like receptors in systemic autoimmune disease. Nature Rev. Immunol. 6, 823–835 (2006).
  Article CAS Google Scholar
• Barton, G. M. Viral recognition by Toll-like receptors. Semin. Immunol. 19, 33–40 (2007).
  Article CAS Google Scholar
• Boule, M. W. et al. Toll-like receptor 9-dependent and -independent dendritic cell activation by chromatin–immunoglobulin G complexes. J. Exp. Med. 199, 1631–1640 (2004).
  Article CAS Google Scholar
• Lau, C. M. et al. RNA-associated autoantigens activate B cells by combined B cell antigen receptor/Toll-like receptor 7 engagement. J. Exp. Med. 202, 1171–1177 (2005).
  Article CAS Google Scholar
• Leadbetter, E. A. et al. Chromatin–IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature 416, 603–607 (2002).
  Article CAS Google Scholar
• Berland, R. et al. Toll-like receptor 7-dependent loss of B cell tolerance in pathogenic autoantibody knockin mice. Immunity 25, 429–440 (2006).
  Article CAS Google Scholar
• Christensen, S. R. et al. Toll-like receptor 9 controls anti-DNA autoantibody production in murine lupus. J. Exp. Med. 202, 321–331 (2005).
  Article CAS Google Scholar
• Christensen, S. R. et al. Toll-like receptor 7 and TLR9 dictate autoantibody specificity and have opposing inflammatory and regulatory roles in a murine model of lupus. Immunity 25, 417–428 (2006).
  Article CAS Google Scholar
• Lande, R. et al. Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature 449, 564–569 (2007).
  Article CAS Google Scholar
• Pisitkun, P. et al. Autoreactive B cell responses to RNA-related antigens due to TLR7 gene duplication. Science 312, 1669–1672 (2006).
  Article CAS Google Scholar
• Subramanian, S. et al. A Tlr7 translocation accelerates systemic autoimmunity in murine lupus. Proc. Natl Acad. Sci. USA 103, 9970–9975 (2006).
  Article CAS Google Scholar
• Hacker, H. et al. CpG-DNA-specific activation of antigen-presenting cells requires stress kinase activity and is preceded by non-specific endocytosis and endosomal maturation. Embo J. 17, 6230–6240 (1998). This paper is the first to describe the requirement for internalization of TLR9 ligands.
  Article CAS Google Scholar
• Ewaschuk, J. B. et al. Surface expression of Toll-like receptor 9 is upregulated on intestinal epithelial cells in response to pathogenic bacterial DNA. Infect. Immun. 75, 2572–2579 (2007).
  Article CAS Google Scholar
• Honda, K. et al. Spatiotemporal regulation of MyD88–IRF-7 signalling for robust type-I interferon induction. Nature 434, 1035–1040 (2005).
  Article CAS Google Scholar
• Latz, E. et al. TLR9 signals after translocating from the ER to CpG DNA in the lysosome. Nature Immunol. 5, 190–198 (2004). This paper is the first to suggest that TLR9 is an ER-resident protein with unique trafficking properties.
  Article CAS Google Scholar
• Leifer, C. A. et al. TLR9 is localized in the endoplasmic reticulum prior to stimulation. J. Immunol. 173, 1179–1183 (2004).
  Article CAS Google Scholar
• Matsumoto, M. et al. Subcellular localization of Toll-like receptor 3 in human dendritic cells. J. Immunol. 171, 3154–3162 (2003).
  Article CAS Google Scholar
• Barton, G. M., Kagan, J. C. & Medzhitov, R. Intracellular localization of Toll-like receptor 9 prevents recognition of self DNA but facilitates access to viral DNA. Nature Immunol. 7, 49–56 (2006).
  Article CAS Google Scholar
• Kim, Y. M., Brinkmann, M. M., Paquet, M. E. & Ploegh, H. L. UNC93B1 delivers nucleotide-sensing toll-like receptors to endolysosomes. Nature 452, 234–238 (2008). This paper implicates UNC93B1 in the trafficking of TLR9 from the ER to endolysosomes.
  Article CAS Google Scholar
• Ewald, S. E. et al. The ectodomain of Toll-like receptor 9 is cleaved to generate a functional receptor. Nature 456, 658–662 (2008).
  Article CAS Google Scholar
• Park, B. et al. Proteolytic cleavage in an endolysosomal compartment is required for activation of Toll-like receptor 9. Nature Immunol. 9, 1407–1414 (2008). References 32 and 33 report that TLR9 is cleaved in its extracellular domain prior to activation.
  Article CAS Google Scholar
• Brinkmann, M. M. et al. The interaction between the ER membrane protein UNC93B and TLR3, 7, and 9 is crucial for TLR signaling. J. Cell Biol. 177, 265–275 (2007).
  Article CAS Google Scholar
• Tabeta, K. et al. The Unc93b1 mutation 3d disrupts exogenous antigen presentation and signaling via Toll-like receptors 3, 7 and 9. Nature Immunol. 7, 156–164 (2006). This paper shows that UNC93B1 is necessary for function of the intracellular TLRs.
  Article CAS Google Scholar
• Asagiri, M. et al. Cathepsin K-dependent Toll-like receptor 9 signaling revealed in experimental arthritis. Science 319, 624–627 (2008). This paper reports a role for cathepsin K in TLR9 signalling.
  Article CAS Google Scholar
• Matsumoto, F. et al. Cathepsins are required for Toll-like receptor 9 responses. Biochem. Biophys. Res. Commun. 367, 693–699 (2008). This paper provides the first evidence that cathepsins are involved in TLR9 activation.
  Article CAS Google Scholar
• Latz, E. et al. Ligand-induced conformational changes allosterically activate Toll-like receptor 9. Nature Immunol. 8, 772–779 (2007).
  Article CAS Google Scholar
• Bell, J. K., Askins, J., Hall, P. R., Davies, D. R. & Segal, D. M. The dsRNA binding site of human Toll-like receptor 3. Proc. Natl Acad. Sci. USA 103, 8792–8797 (2006).
  Article CAS Google Scholar
• Kawai, T. & Akira, S. Innate immune recognition of viral infection. Nature Immunol. 7, 131–137 (2006).
  Article CAS Google Scholar
• Fitzgerald, K. A. et al. Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction. Nature 413, 78–83 (2001).
  Article CAS Google Scholar
• Fitzgerald, K. A. et al. LPS–TLR4 signaling to IRF-3/7 and NF-κB involves the Toll adapters TRAM and TRIF. J. Exp. Med. 198, 1043–1055 (2003).
  Article CAS Google Scholar
• Horng, T., Barton, G. M. & Medzhitov, R. TIRAP: an adapter molecule in the Toll signaling pathway. Nature Immunol. 2, 835–841 (2001).
  CAS Google Scholar
• Medzhitov, R. et al. MyD88 is an adaptor protein in the hToll/IL-1 receptor family signaling pathways. Mol. Cell 2, 253–258 (1998).
  Article CAS Google Scholar
• Oshiumi, H., Matsumoto, M., Funami, K., Akazawa, T. & Seya, T. TICAM-1, an adaptor molecule that participates in Toll-like receptor 3-mediated interferon-β induction. Nature Immunol. 4, 161–167 (2003).
  Article CAS Google Scholar
• Yamamoto, M. et al. Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science 301, 640–643 (2003).
  Article CAS Google Scholar
• Yamamoto, M. et al. TRAM is specifically involved in the Toll-like receptor 4-mediated MyD88-independent signaling pathway. Nature Immunol. 4, 1144–1150 (2003).
  Article CAS Google Scholar
• Yamamoto, M. et al. Cutting edge: a novel Toll/IL-1 receptor domain-containing adapter that preferentially activates the IFN-β promoter in the Toll-like receptor signaling. J. Immunol. 169, 6668–6672 (2002).
  Article CAS Google Scholar
• Horng, T., Barton, G. M., Flavell, R. A. & Medzhitov, R. The adaptor molecule TIRAP provides signalling specificity for Toll-like receptors. Nature 420, 329–333 (2002).
  Article CAS Google Scholar
• Yamamoto, M. et al. Essential role for TIRAP in activation of the signalling cascade shared by TLR2 and TLR4. Nature 420, 324–329 (2002).
  Article CAS Google Scholar
• Hemmi, H., Kaisho, T., Takeda, K. & Akira, S. The roles of Toll-like receptor 9, MyD88, and DNA-dependent protein kinase catalytic subunit in the effects of two distinct CpG DNAs on dendritic cell subsets. J. Immunol. 170, 3059–3064 (2003).
  Article CAS Google Scholar
• Kawai, T. et al. Interferon-α induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6. Nature Immunol. 5, 1061–1068 (2004).
  Article CAS Google Scholar
• Kagan, J. & Medzhitov, R. Phosphoinositide-mediated adaptor recruitment controls Toll-like receptor signaling. Cell 125, 943–955 (2006). This paper provides the first evidence that TLR adaptors can interact with phosphoinositides, and the authors put forward the sorting adaptor hypothesis to distinguish the functions of TIRAP and MYD88 in TLR signalling.
  Article CAS Google Scholar
• Kagan, J. et al. TRAM couples endocytosis of Toll-like receptor 4 to the induction of interferon-β. Nature Immunol. 9, 361–368 (2008). This paper provides the first evidence that TLR4 induces its two signalling pathways sequentially, by a process coordinated around the endocytosis of the receptor.
  Article CAS Google Scholar
• Peter, U., Frank, P., Rudi, B. & Jan, T. MAPPIT analysis of TLR adaptor complexes. FEBS Lett. 581, 629–636 (2007).
  Article Google Scholar
• Oshiumi, H. et al. TIR-containing adapter molecule (TICAM)-2, a bridging adapter recruiting to Toll-like receptor 4 TICAM-1 that induces interferon-β. J. Biol. Chem. 278, 49751–49762 (2003).
  Article CAS Google Scholar
• Rowe, D. C. et al. The myristoylation of TRIF-related adaptor molecule is essential for Toll-like receptor 4 signal transduction. Proc. Natl Acad. Sci. USA 103, 6299–6304 (2006).
  Article CAS Google Scholar
• Palsson-McDermott, E. M. et al. TAG, a splice variant of the adaptor TRAM, negatively regulates the adaptor MyD88-independent TLR4 pathway. Nature Immunol. 10, 579–586 (2009).
  Article CAS Google Scholar
• Janssens, S., Burns, K., Vercammen, E., Tschopp, J. & Beyaert, R. MyD88S, a splice variant of MyD88, differentially modulates NF-κB- and AP-1-dependent gene expression. FEBS Lett. 548, 103–107 (2003).
  Article CAS Google Scholar
• De Matteis, M. A. & Godi, A. PI-loting membrane traffic. Nature Cell Biol. 6, 487–492 (2004).
  Article CAS Google Scholar
• Tanimura, N., Saitoh, S., Matsumoto, F., Akashi-Takamura, S. & Miyake, K. Roles for LPS-dependent interaction and relocation of TLR4 and TRAM in TRIF-signaling. Biochem. Biophys. Res. Commun. 368, 94–99 (2008). This paper shows that endosomes are the sites where the TRAM and TRAF3 signalling proteins converge to promote type I IFN production.
  Article CAS Google Scholar
• Gould, G. W. & Lippincott-Schwartz, J. New roles for endosomes: from vesicular carriers to multi-purpose platforms. Nature Rev. Mol. Cell Biol. 10, 287–292 (2009).
  Article CAS Google Scholar
• Matsuzawa, A. et al. Essential cytoplasmic translocation of a cytokine receptor-assembled signaling complex. Science 321, 663–668 (2008).
  Article CAS Google Scholar